Consumer medicine information

DBL Remifentanil Powder for Injection

Remifentanil

BRAND INFORMATION

Brand name

DBL Remifentanil

Active ingredient

Remifentanil

Schedule

What is in this leaflet?

This leaflet answers some common questions about DBL Remifentanil powder for injection. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given DBL Remifentanil powder for injection against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DBL Remifentanil powder for injection is used for

DBL Remifentanil powder for injection is an anaesthetic used with other anaesthetic medicines, to produce and/or maintain heavy sleep during your operation. If you are a cardiac patient, it may also be used to help relieve any pain immediately following your operation.

DBL Remifentanil powder for injection may also be used for patients in the Intensive Care Unit to maintain sedation and relieve pain.

DBL Remifentanil powder for injection belongs to a group of medicines called opioids. It differs from other medicines in this group by its very quick onset and very short duration of action.

Your doctor may have prescribed DBL Remifentanil powder for injection for another reason.

Ask your doctor if you have any questions about why DBL Remifentanil powder for injection has been prescribed for you.

As with other opioids, DBL Remifentanil powder for injection can be addictive. This is unlikely to happen when DBL Remifentanil powder for injection is only used during your operation.

Before you are given DBL Remifentanil powder for injection

When you must not receive DBL Remifentanil powder for injection

You must not receive DBL Remifentanil powder for injection if you have ever had an allergic reaction to remifentanil hydrochloride or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:

Wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

Before you receive DBL Remifentanil powder for injection, you must tell your doctor if:

You have had any adverse reactions during an operation.
You have had any type of allergic reaction to opioid medicines (e.g., morphine, fentanyl, pethidine, codeine), or to any medicines used during an operation.
You probably have an increased chance of being allergic to DBL Remifentanil powder for injection if you are allergic to other opioids.
You are allergic to any other medicines or any other substance, such as foods, dyes or preservatives.
You have or have ever had any of the following medical conditions:
- slow heart beat
- low blood pressure
- chest or breathing problems.
You are pregnant, intend to become pregnant, are breast feeding or plan to breast feed.
Like most medicines, DBL Remifentanil powder for injection is not recommended in pregnancy and breast-feeding. However, your doctor will discuss the possible risks and benefits of being given DBL Remifentanil powder for injection if you are pregnant or breast-feeding.

If you have not told your doctor about any of the above, tell them before you are given DBL Remifentanil powder for injection.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Tell your doctor if you have recently been taking medicines for blood pressure or heart problems (known as beta-blockers or calcium channel blockers).

Some medicines, such as benzodiazepines, may interfere with DBL Remifentanil powder for injection. Your doctor or pharmacist will be able to tell you what to do when being given DBL Remifentanil powder for injection with other medicines.

How DBL Remifentanil powder for injection is given

DBL Remifentanil powder for injection can be given into a vein in two ways:

As a slow injection, or
As a slow infusion.

DBL Remifentanil powder for injection will be administered by an anaesthetist or other highly trained doctor. You will never be expected to give yourself this medication. The dosage will vary according to many factors such as your body weight and the type of operation you have.

While you are using DBL Remifentanil powder for injection

Things to be careful of

If you are discharged early, following treatment with DBL Remifentanil powder for injection or any other anaesthetic agents, do not drive or operate machinery.

Side-Effects

Check with your doctor as soon as possible if you have any problems after receiving DBL Remifentanil powder for injection, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, DBL Remifentanil powder for injection can cause some side-effects.

The most commonly reported side-effects are:

slow breathing
breathlessness
slow heart beat
drop in blood pressure
Increased blood pressure which may cause a headache or sensation of warmth/flushing.
muscle stiffness
shivering
nausea
vomiting
aches

Ask your doctor or pharmacist to answer any questions you may have.

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side-effects. You may not experience any of them.

Product description

What DBL Remifentanil powder for injection looks like

DBL Remifentanil powder for injection is supplied as 1mg, 2mg or 5mg of white to off-white powder in a clear, glass vial.

Ingredients

DBL Remifentanil powder for injection contains the active ingredient remifentanil (as hydrochloride) 1mg, 2mg or 5mg per vial. Other ingredients are glycine and Dilute Hydrochloric acid and Sodium Hydroxide. The powder is dissolved in a suitable sterile liquid before use.

DBL Remifentanil powder for injection does not contain gluten or lactose.

Storage

Unopened DBL Remifentanil powder for injection vials are stored below 25°C. The 1mg presentation is protected from light.

Manufacturer

Your DBL Remifentanil powder for injection is supplied by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Further Information

Your doctor or pharmacist is the best person to give you advice on the treatment of your condition.

Do not throw this leaflet away. You may need to read it again.

This leaflet was prepared on December 2019.

The information provided applies only to: DBL™ Remifentanil powder for injection.

DBL™ Remifentanil powder for injection 1 mg: AUST R 195553

DBL™ Remifentanil powder for injection 2 mg: AUST R 195554

DBL™ Remifentanil powder for injection 5 mg: AUST R 195555

Published by MIMS February 2020

BRAND INFORMATION

Brand name

DBL Remifentanil

Active ingredient

Remifentanil

Schedule

1 Name of Medicine

Remifentanil hydrochloride.

6.7 Physicochemical Properties

The log P n-octanol/water is 17.9. Remifentanil HCl possesses no chiral centres.
The chemical name of remifentanil hydrochloride (HCl) is methyl 1-(2-methoxycarbonyl-ethyl)-4 -(phenyl-propionyl-amino)-piperidine-4-carboxylate, hydrochloride.
Molecular Formula: C₂₀H₂₈N₂O₅.HCl.
Molecular Weight: 412.9.

Chemical structure.

CAS number.

132539-07-2.

2 Qualitative and Quantitative Composition

Three strengths are available; 1 mg, 2 mg and 5 mg of remifentanil base (as the hydrochloride salt).

3 Pharmaceutical Form

Powder for injection.
DBL Remifentanil powder for injection is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilised powder for intravenous use.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Remifentanil is a potent, selective, 4-anilidopiperidine mu-opioid agonist with pharmacological action typical of this class of compound. It is distinguished from other 4-anilidopiperidines (fentanyl analogues) by its rapid onset and very short duration of action. The mu-opioid activity of remifentanil is antagonised by naloxone. Remifentanil in humans has a rapid blood brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1 minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of remifentanil occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anaesthetic technique, remifentanil can be rapidly titrated to the desired depth of anaesthesia/ analgesia (e.g. as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection. Remifentanil is a potent opioid, therefore careful adherence (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration of the document) is essential to avoid unacceptable adverse events.

Haemodynamics.

In premedicated patients undergoing anaesthesia, 1 minute infusions of < 2 microgram/kg of remifentanil caused dose dependent hypotension and bradycardia. While additional doses > 2 microgram/kg (up to 30 microgram/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the haemodynamic change is increased in proportion to the blood concentrations achieved. Peak haemodynamic effects occur within 3 to 5 minutes of a single dose of remifentanil or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the haemodynamic effects associated with remifentanil. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil, or the dose of concurrent anaesthetics, or by the administration of fluids or vasopressors.

Respiration.

Remifentanil depresses respiration in a dose related fashion. Unlike other fentanyl analogues, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When remifentanil and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3 hour infusions was more rapid and less variable with remifentanil (see Figure 1).

Spontaneous respiration occurs at blood concentrations of 4 to 5 nanogram/mL in the absence of other anaesthetic agents, for example, after discontinuation of a 0.25 microgram/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anaesthesia, the rate of respiratory recovery depends upon the concurrent anaesthetic; it is fastest after N₂O, slower with propofol, and slowest after isoflurane.

Muscle rigidity.

Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of > 1 microgram/kg administered over 30 to 60 seconds or infusion rates > 0.1 microgram/kg/min. Administration of doses < 1 microgram/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.

Histamine release.

Assays of histamine in patients and normal volunteers have shown no elevation in histamine levels after administration of remifentanil in doses up to 30 microgram/kg over 60 seconds.

Clinical trials.

Clinical trials have demonstrated that remifentanil is unsuitable as a sole agent for induction. For induction, remifentanil should only be used as an opioid adjunct where intubation and mechanical ventilation are intended. Remifentanil is not recommended for use in postoperative analgesia, except for ventilated cardiac surgery patients in an environment where the patient is under the close supervision of medically qualified persons trained in the use of anaesthetic drugs (see Section 4.1 Therapeutic Indications; Section 4.3 Contraindications).
Remifentanil was evaluated in 3,562 patients undergoing general anaesthesia (n = 2,923) and monitored anaesthesia care (n = 639). These patients were evaluated in the following settings: inpatient (n = 2,213) which included cardiovascular (n = 675) and neurosurgical (n = 61), and outpatient (n = 1,349). Three hundred seventy-seven (377) elderly patients (age range 66 to 90 years) and 440 paediatric patients received remifentanil. Of the general anaesthesia patients, 1,132 also received remifentanil as an IV analgesic agent during the immediate postoperative period.

Induction and maintenance of general anaesthesia, inpatient/ outpatient.

The efficacy of remifentanil was investigated in 1,562 patients in 15 randomised, controlled trials as the analgesic component for the induction and maintenance of general anaesthesia. Eight of these studies compared remifentanil to alfentanil, and two studies compared remifentanil to fentanyl. In these studies, doses of remifentanil up to the ED₉₀ were compared to recommended doses (approximately ED₅₀) of alfentanil or fentanyl.

Induction of anaesthesia.

Remifentanil was administered with isoflurane, propofol, or thiopentone for the induction of anaesthesia (n = 1,562). The majority of patients (80%) received propofol as the concurrent agent. Remifentanil reduced the propofol and thiopentone requirements for loss of consciousness. Compared to alfentanil and fentanyl, a higher relative dose of remifentanil resulted in fewer responses to intubation (see Table 14). Overall, hypotension occurred in 5% of patients receiving remifentanil compared to 2% of patients receiving the other opioids.
Remifentanil has been used as a primary agent for the induction of anaesthesia; however, it should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnoea, muscle rigidity, and tachycardia. The administration of an induction dose of propofol or thiopentone or a paralysing dose of a muscle relaxant prior to or concurrently with remifentanil during the induction of anaesthesia markedly decreased the incidence of muscle rigidity from 20% to < 1%.

Use during maintenance of anaesthesia.

Remifentanil was investigated in 929 patients in seven well controlled general surgery studies in conjunction with nitrous oxide, isoflurane, or propofol in both inpatient and outpatient settings. These studies demonstrated that remifentanil could be dosed to high levels of opioid effect and rapidly titrated to optimise analgesia intraoperatively without delaying or prolonging recovery. Remifentanil was inadequate as a sole agent for maintenance of anaesthesia.
Compared to alfentanil and fentanyl, these higher relative doses (ED₉₀) of remifentanil resulted in fewer responses to intraoperative stimuli (see Table 15) and a higher frequency of hypotension (16% compared to 5% for the other opioids). Remifentanil was infused to the end of surgery, while alfentanil was discontinued 5 to 30 minutes before the end of surgery as recommended. The mean final infusion rates of remifentanil were between 0.25 and 0.48 microgram/kg/min.

In three randomised, controlled studies (n = 407) during general anaesthesia, remifentanil attenuated the signs of light anaesthesia within a median time of 3 to 6 minutes after bolus doses of 1 microgram/kg with or without infusion rate increases of 50% to 100% (up to a maximum rate of 2 microgram/kg/min).
In an additional double blind, randomised study (n = 103), a constant rate (0.25 microgram/kg/min) of remifentanil was compared to doubling the rate to 0.5 microgram/kg/min approximately 5 minutes before the start of the major surgical stress event. Doubling the rate decreased the incidence of signs of light anaesthesia from 67% to 8% in patients undergoing abdominal hysterectomy, and from 19% to 10% in patients undergoing radical prostatectomy. In patients undergoing laminectomy the lower dose was adequate.

Recovery.

In 2,169 patients receiving remifentanil for periods up to 16 hours, recovery from anaesthesia was rapid, predictable, and independent of the duration of the infusion of remifentanil. In the seven controlled, general surgery studies, extubation occurred in a median of 5 minutes (range: -3 to 17 minutes in 95% of patients) in outpatient anaesthesia and 10 minutes (range: 0 to 32 minutes in 95% of patients) in inpatient anaesthesia. Recovery in studies using nitrous oxide or propofol was faster than in those using isoflurane as the concurrent anaesthetic. There was no case of remifentanil induced delayed respiratory depression (occurring more than 30 minutes after discontinuation of remifentanil).
In a double blind, randomised study, administration of morphine sulfate (0.15 mg/kg) intravenously 20 minutes before the anticipated end of surgery to 98 patients did not delay recovery of respiratory drive in patients undergoing major surgery with remifentanil-propofol total IV anaesthesia.

Paediatric anaesthesia.

The safety, efficacy and pharmacokinetics of remifentanil have been established in five studies which included 687 paediatric patients (aged 5 days to 17 years). Of these, 437 patients received remifentanil: 65 patients were enrolled in pharmacokinetic studies and 372 paediatric patients were studied undergoing general anaesthesia for routine surgical procedures in the inpatient (n = 190) and outpatient (n = 182) settings. Two hundred and fifty patients were administered comparator anaesthetic regimens. Four of the these studies were open labelled.
One randomised, double blind, parallel comparator controlled study consisted of 206 patients, of which 103 received remifentanil. This study found the median time to extubation was 9 minutes vs 10 minutes for fentanyl. The overall incidences of adverse events were 38% for remifentanil and 39% for fentanyl, drug related adverse events were 19% and 22%, respectively.
The studies confirmed the effectiveness of the initial adult dosing in paediatric patients > 1 year of age with subsequent titration to clinical effect according to individual patient requirements. Remifentanil based anaesthesia was shown to be as effective as conventional anaesthetic regimens in attenuation of responses to stimulating procedures and the provision of intraoperative haemodynamic stability. Remifentanil could be continued until the end of surgery and recovery from anaesthesia was rapid, predictable and similar to conventional anaesthetic regimens. Generally higher postoperative pain scores were observed when using remifentanil, consistent with the rapid offset of action of remifentanil. This highlights that longer acting analgesia must be established at an appropriate time in advance of the discontinuation of remifentanil to minimise postoperative pain (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).
No relationship was found between age and the final infusion rate of remifentanil, indicating that the starting dose was appropriate across the range of ages studied. There were no clinically significant differences in time to extubation or other recovery parameters between remifentanil based anaesthesia and conventional anaesthetic regimens. Remifentanil was well tolerated and the incidence of adverse events at the recommended maintenance doses in combination with inhalational anaesthetics was similar to that reported in adults.

Cardiac surgery.

In preliminary investigations of cardiac anaesthesia, two studies evaluated the pharmacokinetics of remifentanil in patients (n = 25) undergoing hypothermic CABG surgery; and two dose ranging studies were conducted which included a total of 217 ASA II-IV patients undergoing CABG surgery. The data indicated that high dose remifentanil (starting doses 1-3 microgram/kg/min) effectively attenuated responses to major surgical stress and was associated with a rapid recovery profile. However, none of these studies included comparator opioids.
Subsequently remifentanil was evaluated in four randomised, double blind studies including a total of 830 patients (450 remifentanil, 380 comparator opioid) undergoing coronary artery bypass graft (CABG) or valve replacement/ repair surgery. This was initiated to develop dosing guidelines for use of remifentanil in cardiac patients, establish the safety and efficacy of remifentanil compared with the use of fentanyl and sufentanil in 'fast-track' cardiac anaesthesia; and especially in higher risk cardiac patients - those with impaired left ventricular function (ejection fraction < 0.35) or undergoing valve surgery.
A high dose remifentanil based regimen was generally more effective in attenuating major surgical stress responses compared to conventional opioid regimens (low/ medium intermittent dose) used for 'fast-track' cardiac surgery (e.g. attenuation of response to maximal sternal spread was 11-21% with remifentanil vs 44-52% fentanyl and 39% sufentanil). Comparable haemodynamic stability was observed during surgery with remifentanil and comparator opioid regimens. After induction and during maintenance, remifentanil was associated with a higher incidence of hypotension or requirement for treatment of excessive anaesthesia than comparator opioid regimens.
Continuation of a remifentanil regimen at a fixed rate of 1 microgram/kg/min into the immediate postoperative period (ICU) was effective in managing patient comfort. The protocol regimen for transition to alternative analgesia in advance of down titration and discontinuation from remifentanil during weaning for extubation, was effective. Although sedation was increased it did not result in significant delay in postoperative recovery. Times to discharge from an intensive care setting were comparable to 'fast-track' opioid regimens.
For the side effect profile in cardiac surgery, see Section 4.8 Adverse Effects (Undesirable Effects).

Neurosurgery.

Remifentanil was administered to 61 patients undergoing craniotomy for removal of a supratentorial mass lesion. In these studies, ventilation was controlled to maintain a predicted PaCO₂ of approximately 28 mmHg. In one study (n = 30) with remifentanil and 66% nitrous oxide, the median time to extubation and to patient response to verbal commands was 5 minutes (range -1 to 19 minutes). Intracranial pressure and cerebrovascular responsiveness to carbon dioxide were normal.
A randomised, controlled study compared remifentanil (n = 31) to fentanyl (n = 32). Remifentanil (1 microgram/kg/min) and fentanyl (2 microgram/kg/min) were administered after induction with thiopentone and pancuronium. A similar number of patients (6%) receiving remifentanil and fentanyl had hypotension during induction. Anaesthesia was maintained with nitrous oxide and remifentanil at a mean infusion rate of 0.23 microgram/kg/min (range 0.1 to 0.4) compared with a fentanyl mean infusion rate of 0.04 microgram/kg/min (range 0.02 to 0.07). Supplemental isoflurane was administered as needed. The patients receiving remifentanil required a lower mean isoflurane dose (0.07 MAC hours) compared with 0.64 MAC hours for the fentanyl patients (P = 0.04). Remifentanil was discontinued at the end of anaesthesia, whereas fentanyl was discontinued at the time of bone flap replacement (a median time of 44 minutes before the end of surgery). Median time to extubation was similar (5 and 3.5 minutes, respectively, with remifentanil and fentanyl). None of the patients receiving remifentanil required naloxone compared to seven of the fentanyl patients (P = 0.01). Eighty one percent (81%) of patients receiving remifentanil recovered (awake, alert, and oriented) within 30 minutes after surgery compared with 59% of fentanyl patients (P = 0.06). At 45 minutes, recovery rates were similar (81% and 69%, respectively for remifentanil and fentanyl, P = 0.27). Patients receiving remifentanil required an analgesic for headache sooner than fentanyl patients (median of 35 minutes compared with 136 minutes, respectively [P = 0.04]). No adverse cerebrovascular effects were seen in this study.

Intensive care unit.

Three clinical studies were conducted to determine the safety and efficacy of remifentanil in a clinically relevant Intensive care population requiring mechanical ventilation for up to three days. Two of these studies (USA03206 and USA30207) were randomised, double blind, controlled, parallel group studies, the third of these (USA30212) was an open labelled, noncomparator study. A total of 261 patients received remifentanil, 81 received fentanyl and 83 received morphine. Of those receiving remifentanil, 32 were treated for ≥ 48 hours, 12 of whom had moderate/ severe renal impairment.
The randomized, double blind studies compared a remifentanil based analgesia/sedation regimen with fentanyl or morphine based regimens. The opioid was initially titrated to achieve adequate levels for sedation (a patient who was calm, easily rousable and followed commands) and analgesia (no or mild pain). Frequent monitoring of the depth of sedation and analgesia was undertaken. Administration of sedative agent was initiated only if the target level of sedation could not be achieved with opioid alone.
A remifentanil based regimen was effective in providing optimal sedation for the majority (82%-90%) of the maintenance phase. Fentanyl and morphine comparator regimens provided similar efficacy in terms of duration of optimal sedation. Remifentanil infusion alone provided optimal sedation in the majority (65% in USA30206, 78% in USA30207 and 43% in USA30212) of patients without the need for a supplementary sedative agent.
The primary end point, between patient variability in the percentage of hours of optimal sedation, was not statistically significantly different for remifentanil compared with fentanyl (study USA30206) or morphine (study USA30207).
Remifentanil was effective in providing adequate analgesia (no pain/ mild pain) for the majority (> 94%) of the maintenance phase. Fentanyl and morphine provided similar efficacy in terms of duration of adequate analgesia. Moderate/ severe pain was reported in a higher percentage of patients administered remifentanil compared to those administered morphine and fentanyl subsequent to down titration and discontinuation of the opioid. This was consistent with the rapid offset of the analgesic effects of remifentanil.
The time to extubation was rapid and comparable between remifentanil and the comparator regimens (median values ≤ 1.3 h in studies USA30206 and USA30207).
Remifentanil was associated with acceptable haemodynamic stability during the maintenance phase, which was similar to that observed in patients administered morphine or fentanyl. A greater incidence of haemodynamic changes were reported in the extubation, post extubation and post treatment phases in the remifentanil group, which were related to a greater incidence of pain.
The data indicate that a remifentanil based regimen (starting infusion rate 0.1-0.15 microgram/kg/min), was very effective for establishing and maintaining optimal analgesia and sedation in a wide range of IC patients, including those with severe renal impairment. In the majority of patients (≥ 60%) in the comparator studies there was no requirement for infusion of supplementary sedative agents (midazolam or propofol) to maintain optimal sedation (SAS 4). In study USA30212, where patients could be more deeply sedated (SAS 2-4), there was a greater requirement for supplementary use of sedative i.e. 58% of patients required propofol infusion. Use of a remifentanil based regimen resulted in rapid extubation of the patients, similar to the comparator opioid regimens.

5.2 Pharmacokinetic Properties

Absorption.

Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0.1 microgram/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2.5 nanogram/mL. Unlike other fentanyl analogues, the duration of action does not increase with prolonged administration.

Distribution.

The central volume of distribution is 100 mL/kg, and the steady-state volume of distribution is 350 mL/kg. Remifentanil is approximately 70% bound to plasma proteins.

Metabolism.

Remifentanil is an esterase metabolised opioid. It is rapidly and extensively metabolised by nonspecific esterases in blood and tissues to the carboxylic acid derivative, GR90291. This metabolite is 4,600 times less active than the parent compound in quantitative EEG analysis of opioid activity.
It is unlikely that there is any clinically significant activity of the metabolite. The half-life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase.

Excretion.

Following administration of the recommended doses of remifentanil, the effective biological half-life is 3-10 minutes due to redistribution. The terminal half-life of the unchanged drug is 10 to 20 minutes. The average clearance of remifentanil in young healthy adults is 40 mL/min/kg. Clearance generally correlates with total body weight (with the exception of severely obese patients in whom it correlates with ideal body weight).

Placental and milk transfer.

Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and/or its metabolites during growth and development. Remifentanil related material is transferred to the milk of lactating rats. In a human clinical trial, the concentration of remifentanil in foetal blood was approximately 50% of that in maternal blood. The foetal arterio-venous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.

Cardiac anaesthesia.

The clearance of remifentanil is reduced by approximately 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree Celsius.

Pharmacokinetics in patients with renal impairment.

After 72 hours of infusion, the rapid recovery from remifentanil based sedation and analgesia is unaffected by mild renal impairment and may be slightly prolonged in patients with moderate/ severe renal impairment (median time to off set of effects of remifentanil was 30 minutes in patients with moderate/ severe renal impairment compared with 13.5 minutes in mild renal impairment).
The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting.
The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. In intensive care patients with moderate/ severe renal impairment, the concentration of the carboxylic acid metabolite may exceed 200-fold the level of remifentanil at steady-state in some patients. There is no evidence that the metabolite produces clinically relevant mu-opioid effects even after administration of remifentanil infusions for up to three days in these patients. However, due to the limited data available, it is not known whether the accumulated metabolite has any other clinically relevant effects (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Intensive care unit).
There is no evidence that remifentanil is extracted during renal replacement therapy.
The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

Pharmacokinetics in patients with hepatic impairment.

The pharmacokinetics of remifentanil is not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery. Individuals with severe hepatic impairment demonstrated statistically significant, reduced sensitivity to carbon dioxide stimulation of minute ventilation, which may indicate an increased sensitivity to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil should be titrated to the individual patient's need.

Pharmacokinetics in paediatric patients.

In paediatric patients 5 days to 17 years of age, the average clearance and steady-state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The half-life of remifentanil is not significantly different in neonates suggesting that changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to that seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2-17 years of age are similar to those seen in adults after correcting for differences in body weight.

Pharmacokinetics in elderly patients.

The clearance of remifentanil is reduced (approximately 25%) in elderly patients (> 65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. The EC₅₀for formation of delta waves on the electroencephalogram (EEG) in elderly patients receiving remifentanil is 50% lower than in young patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient's need.

5.3 Preclinical Safety Data

Genotoxicity.

Remifentanil was not mutagenic in bacterial assays for gene mutations (Salmonella typhimurium histidine reversion assay), chromosomal aberrations (mouse micronucleus and Chinese hamster ovary chromosome) and a DNA repair assay (rat hepatocytes). However, a positive result was obtained in the mouse lymphoma L5178Y/tk+/- assay in the presence of metabolic activation.

Carcinogenicity.

There is no information currently available on the carcinogenic potential of remifentanil.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Remifentanil powder for injection is indicated:
As an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical procedures including cardiac surgery in adults.
As an opioid adjunct for use during induction and/or maintenance of general anaesthesia during surgical but not cardiac procedures in children aged 1 to 12 years.
For continuation as an analgesic into the immediate postoperative period under the close supervision of medically qualified persons trained in the use of anaesthetic drugs, during transition to longer acting analgesia following adult cardiac surgery, when endotracheal intubation and controlled ventilation are anticipated.
For provision of analgesia and sedation in mechanically ventilated intensive care patients.

4.3 Contraindications

DBL Remifentanil powder for injection is not suitable as the sole agent for induction of general anaesthesia.
DBL Remifentanil powder for injection is not recommended for use in spontaneous ventilation anaesthesia or as an analgesic in the immediate postoperative period due to inadequate safety data in such uses, except in ventilated cardiac surgery patients (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration, 2. Cardiac anaesthesia).
As glycine is present in the formulation, DBL Remifentanil powder for injection is contraindicated for epidural and intrathecal use.
DBL Remifentanil powder for injection is contraindicated in patients with known hypersensitivity to any component of the preparation and to other fentanyl analogues.

4.4 Special Warnings and Precautions for Use

As with all opioids, DBL Remifentanil powder for injection is not recommended for use as the sole agent in general anaesthesia.
The use of remifentanil may be associated with apnoea and respiratory depression. Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include intubation and assisted ventilation.

Muscle rigidity, prevention and management.

At the recommended doses, remifentanil can cause muscle rigidity. Profound chest wall rigidity and inability to ventilate the patient has occurred during induction, and following inadvertent boluses after intravenous line flushing. The incidence of muscle rigidity is related to the dose and rate of administration. Therefore, boluses should be administered slowly, over 60 seconds.
Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures. Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents and may require intubation for ventilation. Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil. Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of DBL Remifentanil powder for injection. In the case of life threatening muscle rigidity, a rapid onset neuromuscular blocker or an opioid antagonist may be administered.

Respiratory depression, management.

The use of remifentanil may be associated with apnoea and respiratory depression. Therefore remifentanil should only be used where facilities for monitoring and treating respiratory depression are available. The occurrence of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50% or a temporary discontinuation of the infusion. Remifentanil has not been shown to cause recurrent respiratory depression even after prolonged administration. However, respiratory depression may occur in some patients up to 30 minutes after cessation of the remifentanil infusion due to residual effects of concomitant anaesthetics, and therefore it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area (see Section 4.4 Special Warnings and Precautions for Use, Inadvertent administration).

Cardiovascular effects.

Remifentanil causes dose dependent hypotension and bradycardia. These effects may be attenuated by the pre-administration of an appropriate anticholinergic agent such as glycopyrrolate or atropine. Hypotension and bradycardia may be managed by reducing the rate of infusion of remifentanil or the dose of concurrent anaesthetics, and by using intravenous fluids, vasopressor or anticholinergic agents as appropriate.
Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Rapid offset of action.

Within 5 to 10 minutes after the discontinuation of remifentanil no residual opioid activity will be present. For those patients undergoing surgical procedures where postoperative pain is generally anticipated alternative analgesics should be administered prior to the discontinuation of remifentanil. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care.

Discontinuation of treatment.

Symptoms including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of remifentanil. Where reported, reintroduction and tapering of the infusion has been beneficial.

Inadvertent administration.

A sufficient amount of remifentanil may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs. Remifentanil should be administered, where possible via a dedicated IV line which is removed when remifentanil is discontinued, otherwise into a fast flowing IV line at or close to the venous cannula and primed, in order to avoid administration of drug into the single dead space.

Drug abuse.

As with other opioids, remifentanil may produce dependency.

Awareness.

Intraoperative awareness has been reported when remifentanil has been administered with propofol infusion rates less than 75 microgram/kg/min for TIVA.

Use in obstetrics.

The safety profile of remifentanil during labour or delivery has not been demonstrated. Remifentanil should not be used during labour and caesarean sections because it is known that remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the infant.

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects.

Paediatric use.

Paediatric patients under 1 year of age.

There are insufficient data available on use in paediatric patients under 1 year of age.

Effects on laboratory tests.

There are no known effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Remifentanil is not metabolised by plasma cholinesterase therefore interactions with drugs metabolised by this enzyme are not anticipated.
As with other opioids, remifentanil decreases the dose of inhaled and intravenous anaesthetics and benzodiazepines required for anaesthesia (see Section 4.2 Dose and Method of Administration). If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.
The cardiovascular effects of remifentanil (hypotension and bradycardia), may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Daily administration of remifentanil to male rats was associated with pathological changes in the epididymides at exposures to remifentanil and its major metabolite GR90291 of < 1 and > 200-fold, respectively, at the anticipated clinical exposure, and pathological changes in the testes and reduced fertility and pregnancies at exposures to remifentanil and GR90291 of 1-2 and > 600-fold, respectively, at the anticipated clinical exposure.
(Category C)
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Although placental transfer of remifentanil and its major metabolite GR90291 was found in rats, rabbits and monkeys, there was no evidence of teratogenicity in rats at exposures to remifentanil and its major metabolite of 6 and > 200-fold, respectively, the anticipated clinical exposure. In rabbits, teratogenicity was observed only at remifentanil doses greater than those producing maternotoxicity and foetotoxicity, with remifentanil exposures of about 200-fold anticipated human remifentanil exposure. However, there are no adequate and well controlled studies in pregnant women. The use of remifentanil in pregnant women is not recommended.
It is not known whether remifentanil is excreted in human milk. However, because fentanyl analogues are excreted in human milk and remifentanil related material was found in rat milk after dosing with remifentanil, caution should be exercised when DBL Remifentanil powder for injection is administered to mothers who are breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

The most common adverse events associated with remifentanil are direct extensions of mu-opioid agonist pharmacology, such as respiratory depression, bradycardia, hypotension and skeletal muscle rigidity. These are dose dependent events and hence dissipate within minutes of discontinuing or decreasing the infusion rate of remifentanil. Hypotension may be relatively more common in the elderly (> 65 years). Approximately 3,800 patients have been exposed to remifentanil in controlled clinical trials.
The frequencies of adverse events during general anaesthesia with the recommended doses of remifentanil are given in Table 13. Each patient was counted once for each type of adverse event.

Cardiac anaesthesia.

The side effect profile of remifentanil was consistent with the known pharmacology of mu-opioid agonists. Hypotension observed in maintenance regimens (4% vs 1%); and hypertension (2% vs 0%), shivering (4% vs 2%) and aches (2% vs 0%) observed postoperatively; occurred at a greater frequency with remifentanil compared to "fast-track" comparator opioid (fentanyl and sufentanil) regimens. Although there was a higher frequency of the above adverse events, the incidence of adverse cardiac outcomes in each of the randomised, double blind trials was similar for remifentanil and comparator opioid.

Paediatric anaesthesia.

Remifentanil was well tolerated and the incidence of adverse events at the recommended doses was similar to that reported for adults.

Intensive care unit.

The overall incidence of drug related adverse events across treatment groups was: remifentanil 22% vs fentanyl 17% vs morphine 16%. The incidence of hypotension was comparable between groups (remifentanil 9% vs fentanyl 9% vs morphine 7%); the majority of hypotensive reports being drug related (remifentanil 6% vs fentanyl 6% vs morphine 6%). Episodes of hypotension (defined as a mean arterial pressure, 50 mmHg) were more frequent with remifentanil (11%-17% compared with morphine 2% and fentanyl 10%) however this was not associated with an increase in adverse event reporting. (See Section 4.4 Special Warnings and Precautions for Use, Cardiovascular effects). In the remifentanil group the majority of drug related episodes of hypotension were mild or moderate in severity and in the majority of cases, the average duration was less than 20 minutes.
Pruritus was one of the most commonly reported drug related adverse events in the remifentanil group (2% incidence).

Other adverse events.

Less commonly reported adverse clinical events (incidence < 1%) from all controlled studies are presented below:

Digestive.

Constipation, abdominal discomfort, xerostomia, gastro-oesophageal reflux, dysphagia, diarrhoea, heartburn, ileus.

Cardiovascular.

Various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischaemia, elevated CPK-MB level, syncope.

Musculoskeletal.

Muscle stiffness, musculoskeletal chest pain, postoperative aches.

Respiratory.

Cough, dyspnoea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccups, pulmonary oedema, rales, bronchitis, rhinorrhoea.

Nervous.

Anxiety, involuntary movement, prolonged emergence from anaesthesia, confusion, awareness under anaesthesia without pain, rapid awakening from anaesthesia, tremors, disorientation, dysphoria, nightmares, hallucinations, paraesthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.

Body as a whole.

Decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.

Skin.

Rash, urticaria.

Urogenital.

Urine retention, oliguria, dysuria, urine incontinence.

Infusion site reactions.

Erythema, pruritus, rash.

Metabolic and nutrition.

Abnormal liver function, hyperglycaemia, electrolyte disorders, increased CPK level.

Haematologic and lymphatic.

Anaemia, lymphopaenia, leukocytosis, thrombocytopaenia.

Observed during clinical practice.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anaesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.

Non-site specific.

Very rarely, allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.

Cardiovascular.

Rare cases of asystole/ cardiac arrest, usually preceded by bradycardia, have been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

DBL Remifentanil powder for injection should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include intubation and assisted ventilation.
Continuous infusions of remifentanil must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line. The remifentanil infusion line should be connected at, or close to, the intravenous cannula and primed, to minimise the potential dead space (see Section 4.2 Dose and Method of Administration, Instructions for use for additional information, including tables with examples of infusion rates by body weight to help titrate DBL Remifentanil powder for injection to the patient's anaesthetic needs).
Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use (see Section 4.4 Special Warnings and Precautions for Use). Failure to clear the intravenous tubing to remove residual remifentanil has been associated with the appearance of respiratory depression, apnoea and muscle rigidity upon later administration of fluids or medications through the same IV tubing.
DBL Remifentanil powder for injection is for intravenous use only and must not be administered by epidural or intrathecal injection (see Section 4.3 Contraindications).

Administration by manually controlled infusion.

For manually controlled infusion remifentanil can be diluted to concentrations of 20 to 250 microgram/mL (50 microgram/mL is the recommended dilution for adults and 20 to 25 microgram/mL for paediatric patients aged 1 year and over).

Administration by target controlled infusion.

Remifentanil may also be given by target controlled infusion (TCI) with an approved infusion device incorporating a validated pharmacokinetic model (the Minto pharmacokinetic model with covariates for age and lean body mass (LBM) is an example of a model available with current devices).
TCI can be used for induction and maintenance of ASA I and II adult patients in general and cardiac anaesthesia. There are insufficient data to make recommendations for delivery of remifentanil by TCI for ASA III and IV patients, spontaneous ventilation anaesthesia, use in ICU sedation, monitored conscious sedation or in children.
For TCI in adults the recommended dilution of remifentanil is 20 to 50 microgram/mL.
The administration of DBL Remifentanil powder for injection must be individualised based on the patient's response. It is not recommended for use as the sole agent in general anaesthesia.

Dosage. 1. General anaesthesia.

1.1 Dosage in adults. Administration by manually controlled infusion.

Table 1 summarises the starting infusion rates and dose range for various anaesthetic situations.

(See Section 4.2 Dose and Method of Administration, Instructions for use for additional information, including tables to help titrate DBL Remifentanil powder for injection to the patient's anaesthetic needs.)
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia (see Concomitant medication).
No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil.

Induction of anaesthesia.

Remifentanil should be administered with a hypnotic agent, such as propofol, thiopentone or isoflurane, for the induction of anaesthesia (see Section 4.4 Special Warnings and Precautions for Use, Muscle rigidity, prevention and management). Remifentanil can be administered at an infusion rate of 0.5 to 1 microgram/kg/min with or without an initial bolus injection of 1 microgram/kg over 60 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of remifentanil, then a bolus infusion is not necessary.

Maintenance of anaesthesia in ventilated patients.

After endotracheal intubation, the infusion rate of remifentanil should be decreased, according to anaesthetic technique, as indicated in Table 4. Due to the fast onset and short duration of action of remifentanil, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of mu-opioid response. In response to light anaesthesia, supplemental bolus infusions may be administered every 2 to 5 minutes.

Analgesia.

On cessation of infusion, remifentanil has a short lasting analgesic effect. Postoperative pain management should be considered and, where appropriate, begun prior to the termination of remifentanil infusion.

Guidelines for discontinuation.

Upon discontinuation of remifentanil infusion the intravenous tubing should be cleared to prevent the inadvertent administration of remifentanil at a later point in time (see Section 4.4 Special Warnings and Precautions for Use). Due to the rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of DBL Remifentanil powder for injection. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care.

Concomitant medication.

Remifentanil decreases the dose of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Doses of the following agents used in anaesthesia, isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75% when used concurrently with remifentanil.

Administration by target controlled infusion.

Induction and maintenance of anaesthesia in ventilated patients.

Remifentanil TCI should be used in association with an intravenous or inhalational hyptonic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see Table 1). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 nanogram/mL. Remifentanil should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanogram/mL may be required.
As with manually-controlled infusion, at the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia (see Table 1).
There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.

Guidelines for discontinuation/ continuation into the immediate postoperative period.

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 nanogram/mL. As with manually controlled infusion, postoperative analgesia should be established before the end of surgery with longer acting analgesics (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).
There are insufficient data to make recommendations on the use of TCI for the management of postoperative analgesia.

1.2 Dosage in paediatric patients (1-12 years of age). Administration by manually controlled infusion.

Induction of anaesthesia.

There are insufficient data to make a dosage recommendation.

Maintenance of anaesthesia.

See Table 2.

When given by bolus injection remifentanil should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the remifentanil infusion, if a simultaneous bolus dose has not been given. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Concomitant medication.

At the doses recommended above, remifentanil significantly reduced the amount of hypnotic agent required to maintain anaesthesia. Therefore isoflurane, halothane and sevoflurane should be administered as recommended above to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Concomitant medication).

Guidelines for discontinuation.

Following discontinuation of the infusion, the offset of analgesic effect of remifentanil is rapid and similar to that seen in adult patients. Appropriate postoperative analgesic requirements should be anticipated and implemented (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).

Administration by target controlled infusion.

Remifentanil TCI has not been studied in paediatric patients.

Paediatric patients aged less than 1 year.

The pharmacokinetic profile of remifentanil in paediatric patients aged more than 2 months is comparable to that seen in adults after correction for body weight differences. However, there are insufficient pharmacokinetic and clinical data to make dosage recommendations for patients aged less than 1 year.

2. Cardiac anaesthesia.

2.1 Dosage in adults. Administration by manually controlled infusion.

See Table 3.

Induction period of anaesthesia.

After administration of hypnotic to achieve loss of consciousness, remifentanil should be administered at an initial infusion rate of 1 microgram/kg/min. The use of bolus injections of remifentanil during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 6 minutes after the start of infusion in order to minimise the response to intubation.

Maintenance period of anaesthesia.

After endotracheal intubation the infusion rate of remifentanil should be titrated according to patient need. Supplemental bolus doses may also be given as required. High risk cardiac patients, such as those with poor ventricular function, should be administered a maximum bolus dose of 0.5 microgram/kg. These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see Section 5.2 Pharmacokinetic Properties, Cardiac anaesthesia).

Concomitant medication.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Concomitant medication).

Continuation of postoperative analgesia prior to extubation.

It is recommended that the infusion of remifentanil should be maintained at the final intraoperative rate during transfer of patients to the postoperative care area. Upon arrival into this area, the patient's level of analgesia and sedation should be closely monitored and the remifentanil rate adjusted to meet the individual patient's requirements.

Guidelines for discontinuation.

Remifentanil should only be continued as an analgesic in the immediate postoperative period, and subsequently discontinued during transition to longer acting analgesia, in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by medically qualified persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include intubation, and assisted ventilation.
Prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance. The choice and dose of agent(s) should be appropriate for the patient's level of postoperative care (see Section 4.2 Dose and Method of Administration, Dosage, 1. General anaesthesia, 1.1 Dosage in adults, Administration by manually controlled infusion, Guidelines for discontinuation).
It is recommended that the remifentanil infusion is discontinued by reducing the infusion rate by 25% decrements in at least 10 minute intervals until the infusion is discontinued. During weaning from the ventilator the remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.
It is recommended that haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

Administration by target controlled infusion.

There are insufficient data to make recommendations for delivery of remifentanil by TCI for ASA III and IV patients undergoing cardiac surgery.
There are insufficient data to make recommendation on the use of TCI for the management of postoperative analgesia.

Induction and maintenance of anaesthesia.

Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see Table 3). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanogram/mL have been used in clinical studies. At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia.
Therefore, isoflurane and propofol should be administered as recommended above to avoid excessive depth of anaesthesia (see Table 3).

Guidelines for discontinuation/ continuation into the immediate postoperative period.

2.2 Dosage in paediatric patients.

There are insufficient data to make a dosage recommendation for use during cardiac surgery.

3. Special patient populations.

3.1 Dosage in elderly patients (over 65 years of age).

(a) General anaesthesia.

The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then titrated to individual patient need, as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance and immediate postoperative analgesia.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Section 4.2 Dose and Method of Administration, Dosage, 2. Cardiac anaesthesia, 2.1 Dosage in adults).

Administration by manually controlled infusion.

Intensive care.

No initial dose reduction is required (see Section 4.2 Dose and Method of Administration, Dosage, 3. Special patient populations, 3.7 Use in intensive care).

Administration by target controlled infusion.

General anaesthesia.

Because of the increased sensitivity of elderly patients to remifentanil, when administering remifentanil by TCI in this population the initial target concentrations should be 1.5 to 4 nanogram/mL with subsequent titration to response.

3.2 Dosage in obese patients. Administration by manually controlled infusion.

For manually controlled infusion, it is recommended that for obese patients the dosage of remifentanil should be reduced and based upon ideal body weight as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight in this population.

Administration by target controlled infusion.

With the calculation of lean body mass (LBM) used in the Minto model, LBM is likely to be underestimated in female patients with a body mass index (BMI) greater than 35 kg/m² and in male patients with BMI greater than 40 kg/m². To avoid under dosing in these patients, remifentanil should be titrated carefully to individual response.

3.3 Dosage in patients with renal impairment.

No dosage adjustment, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of remifentanil is unchanged in this patient population.

3.4 Dosage in patients with hepatic impairment.

No adjustment of the initial dose, relative to that used in healthy adults, is necessary as the pharmacokinetic profile of remifentanil is unchanged in this patient population. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil titrated to individual patient needs.

3.5 Neurosurgery.

There is limited clinical experience with patients undergoing neurosurgery.

3.6 ASA III/IV patients.

(a) General anaesthesia.

As the haemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of remifentanil in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended.
Manually controlled infusion: Initial dosage reduction and subsequent titration to effect is therefore recommended.
Target controlled infusion: TCI is not recommended for ASA III or IV patients.

(b) Cardiac anaesthesia.

No initial dose reduction is required (see Section 4.2 Dose and Method of Administration, Dosage, 2. Cardiac anaesthesia, 2.1 Dosage in adults).

(c) Intensive care.

No initial dose reduction is required (see Section 4.2 Dose and Method of Administration, Dosage, 3. Special patient populations, 3.7 Use in intensive care).

3.7 Use in intensive care. Administration by manually controlled infusion. Adults.

Remifentanil can be initially used alone for the provision of analgesia and sedation in mechanically ventilated intensive care patients.
It is recommended that remifentanil is initiated at an infusion rate of 0.1 microgram/kg/min to 0.15 microgram/kg/min. The infusion rate should be titrated in increments of 0.025 microgram/kg/min to achieve the desired level of analgesia and sedation. A period of at least 5 minutes should be allowed between dose adjustments. The level of analgesia and sedation should be carefully monitored, regularly reassessed and the remifentanil infusion rate adjusted accordingly. If an infusion rate of 0.2 microgram/kg/min is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated. The dose of sedative agent should be titrated to obtain the desired level of sedation. Further increases to the remifentanil infusion rate in increments of 0.025 microgram/kg/min may be made if additional analgesia is required.
Remifentanil has been studied in intensive care patients in well controlled clinical trials for up to three days (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Intensive care unit).
Table 4 summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients:

Bolus doses of remifentanil are not recommended in the intensive care setting.
The use of remifentanil will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given in Table 5.

To allow separate titration of the respective agents sedative agents should not be administered as an admixture.

Additional analgesia for ventilated patients undergoing stimulating procedures.

An increase in the existing remifentanil infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that a remifentanil infusion rate of at least 0.1 microgram/kg/min should be maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 microgram/kg/min, maximum 0.75 microgram/kg/min, has been administered for provision of additional anaesthesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of DBL Remifentanil powder for injection.

Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Prior to discontinuation of DBL Remifentanil powder for injection, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse of the patient. These techniques should always be titrated to individual patient need as the infusion of remifentanil is reduced (see below). It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to discontinuation of DBL Remifentanil powder for injection.
In order to ensure a smooth emergence from a remifentanil based regimen it is recommended that the infusion rate of DBL Remifentanil powder for injection is titrated down in stages to 0.1 microgram/kg/min over a period up to 1 hour prior to extubation.
Following extubation, the infusion rate should be reduced by 25% decrements in at least 10 minute intervals until the infusion is discontinued. During weaning from the ventilator the DBL Remifentanil powder for injection infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Paediatric intensive care patients.

There are no data available on use in paediatric patients.

Renally impaired intensive care patients.

No adjustments to the doses recommended above are necessary in renally impaired patients including those undergoing renal replacement therapy.
Recovery following discontinuation of a remifentanil infusion may be slightly prolonged in moderate to severe renal impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment).

Administration by target controlled infusion.

Remifentanil TCI has not been studied in intensive care patients.

Instructions for use.

Reconstitution and dilution.

To reconstitute the powder, add 1 mL of diluent (see Physical compatibilities for recommended diluents) per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL. DBL Remifentanil powder for injection should be diluted to a final concentration of 20, 25, 50, or 250 microgram/mL prior to administration (see Table 6).
50 microgram/mL is the recommended dilution for adults and 20-25 microgram/mL for paediatric patients aged 1 year and over. The dilution is dependent upon the technical capability of the infusion device and the expected requirements of the patient. DBL Remifentanil powder for injection should not be administered without dilution.

Physical compatibilities.

DBL Remifentanil powder for injection is chemically and physically stable and should be used within 24 hours of preparation and storage at 2-8°C, after reconstitution and further dilution to concentrations of 20 to 250 microgram/mL with one of the following recommended intravenous fluids: sterile water for injection, 5% glucose injection, 5% glucose and 0.9% sodium chloride injection, 0.9% sodium chloride injection, 0.45% sodium chloride injection.
DBL Remifentanil powder for injection contains no antimicrobial preservative and care must be taken to assure the sterility of prepared solutions. Reconstituted product should be used promptly and any unused material discarded. If storage is necessary, hold at 2-8°C for not more than 24 hours to reduce microbiological hazard.
(See Physical incompatibilities).
DBL Remifentanil powder for injection has been shown to be compatible with the following intravenous fluids when administered into a running intravenous line: lactated ringer's injection, lactated ringer's and 5% glucose injection.
DBL Remifentanil powder for injection has been shown to be compatible with propofol when administered into a running intravenous line.

Physical incompatibilities.

Continuous infusions of remifentanil must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line.
DBL Remifentanil powder for injection should only be admixed with those infusion solutions recommended (also see Physical compatibilities).
DBL Remifentanil powder for injection should not be admixed with lactated ringer's injection or lactated ringer's and 5% glucose injection.
DBL Remifentanil powder for injection should not be mixed with propofol in the same intravenous admixture solution.
Administration of DBL Remifentanil powder for injection into the same intravenous line with blood/ serum/ plasma is not recommended. Nonspecific esterase in blood products may lead to the hydrolysis of DBL Remifentanil powder for injection to its inactive metabolite.
DBL Remifentanil powder for injection should not be mixed with other therapeutic agents prior to administration.

Administration by manually controlled infusion.

For manually controlled infusion remifentanil can be diluted to concentrations of 20 to 250 microgram/mL (50 microgram/mL is the recommended dilution).
Tables 7, 8, 9, 10 and 11 give guidelines for infusion rates of DBL Remifentanil powder for injection for manually controlled infusion.

Administration by target controlled infusion.

For TCI the recommended dilution of remifentanil is 20 to 50 microgram/mL.
Table 12 gives guidelines for blood concentrations achieved at steady-state with MCI in a 70 kg, 170 cm, 40 year old, male patients (using Minto PK model).

Discontinuation.

Upon discontinuation of remifentanil infusion sufficient drug may remain in intravenous lines or in the dead space of cannulae to cause opioid related effects (e.g. respiratory depression) if the line is flushed. Therefore, appropriate measures should be taken to avoid such inadvertent administration of remifentanil (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

Following treatment using anaesthetic agents, patients should be advised not to drive or operate machinery.

4.9 Overdose

Overdosage is manifested by an extension of the pharmacologically predictable actions of remifentanil.
In the event of overdosage or suspected overdosage, take the following actions: discontinue administration of DBL Remifentanil powder for injection, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressor agents for the treatment of hypotension and other supportive measures may be employed.
Intravenous administration of naloxone may be given as a specific antidote to manage severe respiratory depression and muscle rigidity.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

The product is formulated in glycine and requires reconstitution and dilution before use. Dilute hydrochloric acid and sodium hydroxide are also used as excipients for pH adjustments.

6.2 Incompatibilities

Continuous infusions of remifentanil must be administered by a calibrated infusion device, where possible via a dedicated intravenous line, otherwise into a fast flowing IV line.
DBL Remifentanil powder for injection should only be admixed with those infusion solutions recommended (see Section 4.2 Dose and Method of Administration, Physical compatibilities).
DBL Remifentanil powder for injection should not be admixed with Lactated Ringer's Injection or Lactated Ringer's and 5% Glucose Injection.
DBL Remifentanil powder for injection should not be mixed with propofol in the same intravenous admixture solution.
Administration of DBL Remifentanil powder for injection into the same intravenous line with blood/serum/plasma is not recommended. Non-specific esterase in blood products may lead to the hydrolysis of DBL Remifentanil powder for injection to its inactive metabolite.
DBL Remifentanil powder for injection should not be mixed with other therapeutic agents prior to administration.
(See Section 4.2 Dose and Method of Administration, Physical incompatibilities).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Store below 25°C. The 1 mg presentation should be stored protected from light.

6.4 Special Precautions for Storage

The reconstituted solution is chemically and physically stable for 48 hours at room temperature but since the product includes no preservative, reconstituted product should be used promptly and any unused material discarded. If storage is necessary, hold at 2-8°C for not more than 24 hours to reduce microbiological hazard. Product is for single use in one patient only.

6.5 Nature and Contents of Container

1 mg remifentanil base (as the hydrochloride salt) in 3.5 mL vials in cartons of 5.
2 mg remifentanil base (as the hydrochloride salt) in 3.5 mL vials in cartons of 5.
5 mg remifentanil base (as the hydrochloride salt) in 8 mL vials in cartons of 5.
Container labelled "Single dose".
Packed in clear glass vials with siliconised stoppers and overseals.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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